Adaptation to hypoxic conditions and hyperactivation of the epidermal growth factor receptor (EGFR) are two well-characterized cellular processes that contribute to oncogenesis and poor prognosis in patients with cancer (see Hung et al.). Wang et al. investigated EGFR signaling in clear-cell renal cell carcinoma (CCRCC), which is caused by dysfunction of the E3 ubiquitin ligase, VHL, that targets hypoxia-inducible factor α (HIF-α) subunits for degradation during normoxic conditions. In response to tumor necrosis factor–α (TNF-α) treatment, the half-life of EGFR was longer in the CCRCC cell line 786-O lacking VHL function (VHL–/–; HIF1A–/–; HIF2A+/+) than it was in 786-VHL cells in which VHL was reconstituted or in 786-VHL cells expressing a nondegradable form of HIF-2α. Activation of signaling components downstream of EGFR was also prolonged in the cells in which HIF-2α was stabilized compared with the 287-VHL cells and was associated with reduced apoptosis in response to Fas treatment and increased cell proliferation. Cells in which HIF-2α was stabilized failed to form giant endosomes upon transfection with an activated form of Rab5, and in cells exposed to fluorescently labeled EGF the internalized ligand persisted in cells lacking in VHL. Thus, HIF-2α signaling inhibits movement through the endocytic pathway. Elevated HIF-2α, either due to exposure to low oxygen conditions or loss of VHL function, correlated with reduced abundance of rabaptin-5, which is necessary for Rab5-mediated endosome fusion. Forced expression of rabaptin-5 reduced the half-life of EGFR and decreased cell proliferation in the 786-O cells. The transcript and protein abundance of rabaptin-5 was lower or undetectable in CCRCC compared with nondiseased tissue, and in CCRCC the lower rabaptin-5 transcripts correlated with a hypoxic gene expression signature. The promoter of the rabaptin-5 gene (RABEP1) contains a hypoxia-responsive element, and chromatin immunoprecipitation experiments confirmed that more HIF-2α was present at the promoter in cells in which VHL function was compromised.